PROJECT SUMMARY Primary sclerosing cholangitis (PSC) is an idiopathic disease of the liver characterized by ongoing inflammation of the intrahepatic- and/or extrahepatic bile ducts, which can ultimately lead to cirrhosis and end-stage liver disease (ESLD). It is often associated with inflammatory bowel disease (IBD), namely ulcerative colitis (UC). PSC patients have a reduced survival compared to the general healthy population, and many PSC patients will eventually require liver transplantation (LT) due to complications such as progression to ESLD, development of cholangiocarcinoma (CCA), a primary bile duct cancer that carries a grave prognosis, recurrent acute cholangitis (a serious biliary tree infection), or extreme symptoms related to liver disease (such as fatigue and pruritus). The diagnosis of PSC is made when there is cholestasis and imaging (narrowing and dilatation) or histological (destruction and fibrosis) evidence of PSC. Currently, there is no medical therapy proven to halt the progression of the disease. The cause of PSC is unknown; however, accumulating evidence suggests a link between PSC and the intestinal microbiota (the bacteria that live in the colon). Open-label clinical trials have shown that the use of oral vancomycin (OV) in PSC patients has resulted in normalization of the serum cholestatic marker alkaline phosphatase (ALP), which has been found to be of prognostic importance in PSC. Specifically, normalization of serum ALP appears to be associated with long-term survival free of CCA, the need for LT, or liver-related death in PSC, and persistently elevated ALP over time has been shown to be associated with serious adverse events (development of CCA, liver-related death, and need for LT). Findings from the clinical reports of OV in PSC have prompted us to examine the role of OV as a potential therapeutic agent in PSC in a larger sample of PSC subjects over an extended period. We hypothesize that in PSC patients, daily treatment with OV results in normalization of serum ALP. The results of this clinical trial will help us determine if OV can be used as treatment for PSC patients. The overall goal of this phase II, randomized, placebo-controlled clinical trial is to examine the safety, tolerability and efficacy of daily dosing (over an 18-month period) with OV, using a stepped-up dosing strategy with three increasing doses, on the clinical course, and the progression of PSC, and to compare the treated patients with those on placebo. Study subjects in the OV and placebo arms will be compared with respect to their clinical and laboratory evaluations at the defined study points.